Project Summary Despite therapy with intravenous immunoglobulin (IVIG) plus infliximab, a monoclonal antibody against the pro- inflammatory cytokine tumor necrosis factor (TNF) ?, more than 25% of children with Kawasaki disease (KD), the most common cause of acquired heart disease in children, develop coronary artery abnormalities (CAA) with either dilated or aneurysmal coronary arteries. Once aneurysms have formed, the damage to the arterial wall is irreversible, and over time, stenoses and calcification may lead to ischemic complications. However, there is no recommended therapy to halt the progression of arterial wall damage and prevent aneurysm formation. Thus, the goal of our project is to test a new therapy to attenuate CAA and block progression of early injury to aneurysm formation. In KD, the IL-1 pathway is upregulated, as demonstrated by increased transcript abundance by microarray and by increased levels of pathway proteins in the plasma. In the Lactobacillus casei cell wall extract KD mouse model of coronary arteritis, the IL-1 receptor antagonist, anakinra, prevented the development of CAA, as did knocking out the IL-1 receptor. Given the role of the IL-1 pathway in KD-associated inflammation, blockade of IL-1 with anakinra is a logical therapy to attenuate CAA in KD. Treatment with anakinra has been well-tolerated and has coincided with a decrease in systemic inflammation and CAA in a small number of KD patients. However, despite its increasing off-label use, there are limited data in infants and young children. The proposed Phase I/IIa, dose escalation study will determine if anakinra in children at least 8 months to 17 years of age treated with IVIG and aspirin who have evidence of CAA by echocardiography is safe and well- tolerated (Specific Aim 1). Furthermore, this study will evaluate if anakinra has high bioavailability and whether its pharmacokinetics can be characterized by a one-compartment model using sparse sampling (Specific Aim 2). Lastly, this study will develop a pharmacodynamic biomarker-based model to find the proper dose of anakinra for a sustained anti-inflammatory effect in children with acute KD and CAAs. (Specific Aim3). Understanding the safety, PK, and proper dosing of anakinra to have a sustained anti-inflammatory effect are central to moving forward with a Phase III study and addressing the unmet clinical need of preventing formation or progression of aneurysms in KD.